ABSTRACT Young-onset type 2 diabetes (T2D) is a priority public health issue, since it is often unrecognized, responds poorly to treatment, and results in rapid progression of microvascular and macrovascular complications. Thus, an improved understanding of the factors that trigger young-onset T2D development and pathological progression is needed. This is especially important among Hispanic youth, a minority group with high rates of T2D. Animal studies show that even at low levels of exposure, persistent organic pollutants (POPs), including organochlorine compounds, perfluoroalkyl substances, and brominated flame retardants, contribute to T2D pathogenesis. Human exposure to POPs is widespread and individuals are exposed not only to a single chemical but also to a mixture of environmental chemicals that may have synergistic actions. However, evidence from human studies is inconclusive and largerly based on cross-sectional adult studies examining single exposures. Importantly, no previous study has examined the effects of multiple chemical exposures on longitudinal alterations of glucose metabolism and insulin secretion prior to disease development, a critical period in which interventions have the potential to stop or delay T2D development. Our overarching hypothesis is that the burden of exposure to multiple environmental chemicals may increase susceptibility to T2D in youth. This hypothesis is based on our strong preliminary data and compelling prior evidence from experimental models. Our multidisciplinary team of investigators proposes to test this hypothesis in a discovery longitudinal cohort of Hispanic adolescents at risk for T2D with existing gold standard clinical assessments of glucose homeostasis, insulin secretion, and ?-cell function (the Study of Latino Adolescents at Diabetes Risk, SOLAR), and to replicate findings and examine generalizability in a longitudinal cohort of similar design with a representative sample of Hispanic and non-Hispanic youth (Children Health Study, CHS). In addition, high resolution metabolomics profiles will advance our understanding of the mechanisms underlying the diabetogenic effects of POPs. In both cohorts, we will use novel statistical and bioinformatics methods to predict subgroups of youth at increased risk for T2D based on their exposure to environmental chemicals and metabolomics profiles. Our specific aims are to determine the extent to which POPs exposures are individually and/or jointly associated with: 1) longitudinal alterations of glucose metabolism, insulin sensitivity, and ?-cell function in youth (Aim 1), and 2) impairment in the regulation of lipid and amino acid metabolism pathways associated with increased susceptibility to T2D (Aim 2). Ultimately, we aim to predict subgroups of youth with increased susceptibility to T2D based on their POPs exposure and metabolomics profiles using novel statistical approaches (Aim 3). The study is innovative and offers a unique opportunity to advance our understanding on environmental contributions to T2D and open new avenues for diabetes prevention in youth.